Generation of autoantibodies is a hallmark of autoimmune diseases. Recent data in humans and mice show that overrepresentation of T follicular helper (Tfh) cells, a CD4+ T cell subset specialized in helping B cells in germinal centers (GCs), is associated with autoimmunity. Yet, the immune mechanisms that cause exaggerated Tfh response in human autoimmune diseases remain largely unknown. Our preliminary studies suggest a common mechanism associated with exaggerated Tfh responses in human autoimmune disease. We identified two candidate factors derived from antigen-presenting cells promoting Tfh responses. Altered Tfh response in autoimmune diseases might be also associated with dysregulated of T follicular regulatory (Tfr) cells that originate from thymus-derived regulatory T cells (Tregs). In this Collaborative Project, we hypothesize that Altered APCs promotes Tfh response while suppressing Tfr response thereby contributing to the pathogenesis of human autoimmune diseases. We will share our established methods for the studies of human Tfh cells to other Centers, so that newly diagnosed untreated patients with a broad range of autoimmune diseases can be analyzed across the Centers. The specific aims are AIM 1: To determine the alteration in Tfh cell subsets in blood in autoimmune diseases. AIM 2: To determine the alteration in Tfh cells and CD11c+ APCs in inflammatory tissues in autoimmune diseases. AIM 3: To determine whether APCs in inflammatory tissues are capable of inducing naive and memory CD4+ T cells to differentiate into Tfh cells, and AIM 4: To determine whether and how Tfr response is altered in autoimmune diseases. In conclusion, we might be able to reveal immunological pathways that cause altered Tfh/GC response shared by different autoimmune diseases as well as unique one to each disease.